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Fingolimod-Associated Macular Edema (FAME)

Fingolimod (Gilenya) is the first, and only, oral agent approved for the treatment of multiple sclerosis (MS). In Canada, it is approved as a second-line monotherapy in patients with MS who have had an incomplete response to, or are unable to tolerate, one of the first-line therapies. Gilenya is the first drug in a new class of compounds that targets the sphingosine-1-phosphate receptor. This novel drug has been shown to be the cause of the rare ocular adverse effect: fingolimod-associated macular edema (FAME).

A review of all clinical trials of Gilenya has shown that the prevalence of FAME is less than 1%1. Most cases are unilateral, although bilateral cases can occur1. In most cases, FAME occurs within 4 months of initiation of therapy with Gilenya, but FAME can occur after 12 months or more1. Patients with a history of diabetes or uveitis are more likely to develop FAME1. The majority of cases will resolve spontaneously following discontinuation of the drug, while some cases require treatment with anti-inflammatory medication1,2. Recently published case reports have shown that FAME can be effectively treated (with local anti-inflammatory treatment) in patients who continue taking the medication, thereby avoiding the need to discontinue Gilenya and possibly cause worsening of the MS2-4.

The mechanism whereby Gilenya causes FAME is not known, but may be related to increased vascular permeability1,4. Common causes of macular edema include inflammation (e.g. uveitis) or retinal vascular disease (e.g. diabetic retinopathy). However, patients with FAME do not have concurrent signs of uveitis (cells or flare) or diabetic retinopathy (macular microaneurysms or hard exudates). Optical coherence tomography and fluorescein angiography can be useful imaging modalities in the diagnosis of FAME.

The number of patients with MS who are taking Gilenya is likely to increase significantly in the coming years, and optometrists have an important role in their care. Patients taking Gilenya should be screened regularly by optometrists for the development of macular edema. Any patient suspected of having FAME should be referred to an ophthalmologist with experience in the diagnosis and treatment of macular edema.

“Macular telangiectasia” is a term commonly used to refer to an entity that has previously been referred to as type 2 idiopathic macular telangiectasia (type 2 IMT) or idiopathic juxtafoveal retinal telangiectasia (IJRT). The prevalence of this maculopathy has been estimated to be 0.1%1. The early signs of this disease can be subtle and missed on clinical examination. However, retinal imaging will readily show these signs. While there is no treatment for this condition, recent evidence suggests that dietary supplementation may be beneficial.

CASE DESCPRIPTION

A 40 year-old Caucasian male was referred by a local optometrist for bilateral decreased vision and macular changes. Best-corrected visual acuity was 20/40 in the right eye and 20/50 in the left eye. Slit-lamp examination and intraocular pressures were within normal limits in both eyes. Dilated fundus examination showed the presence of parafoveal graying, intraretinal crystalline deposits, and some subtle vascular changes in the macula of both eyes (Figure 1). Fluorescein angiography clearly showed the leakage from telangiectatic vessels in both eyes (Figure 2), and spectral-domain optic coherence tomography (SD-OCT) showed outer retina atrophy in both eyes (Figure 3).

FIGURE 1: Colour fundus photographs of the right (A) and left (B) eye showing the presence of parafoveal graying, intraretinal crystalline deposits, and subtle vascular changes in the macula.

FIGURE 2: Fluorescein angiogram of the right (A) and left (B) eye showing leakage from telangiectatic vessels.

Macular pigment density measurement showed evidence of decreased macular pigment in both eyes (Figure 4). The patient was diagnosed with macular telangiectasia, and counseled about the nature of his disease.

Macular telangiectasia is a rare maculopathy that is poorly understood and often misdiagnosed. In the early stages, the disease is characterized by telangiectatic vessels, parafoveal graying, intraretinal crystalline deposits, and outer retinal atrophy. In the early stage, macular telangiectasia can be misdiagnosed as diabetic retinopathy. In the later stages of the disease, dilated venules and pigment clumping start to develop (Figure 5). At this stage, the disease may be misdiagnosed as age-related macular degeneration.

FIGURE 5. Colour fundus photographs of the right (A) and left (B) eye of a patient with advanced macular telangiectasia showing macula pigment clumping in both eyes.

One of the key features of this disease is the predilection for the temporal parafoveal region. Therefore, any patient with vascular and pigment abnormalities in the temporal parafovea should be suspected of having macular telangiectasia and referred to a retina specialist.

The pathophysiology of macular telangiectasia is poorly understood. Although one of the hallmarks of the disease is telangiectatic retinal vessels with leakage on fluorescein angiography, this is not a neovascular disease. Furthermore, despite the leakage on seen on fluorescein angiography, these patients do not develop macular edema. Rather, they develop macular atrophy. Not surprisingly, intravitreal anti-VEGF therapy has not proven efficacious for this disease2. Intravitreal anti-VEGF therapy is only effective in patients who develop secondary choroidal neovascularization, which is rare in this condition. Macular telangiectasia is believed to be primarily a degenerative disease of the macula, caused by death of Muller cells within the retina3. The atrophy of the retina can be appreciated on SD-OCT, which clearly shows the outer retinal atrophy. This is a progressive disease, but patients can often maintain reasonable visual function since scotomas tend to be parafoveal and foveal vision may not be as severely affected. There is no treatment for macular telangiectasia. Studies have shown that patients with macular telangiectasia have decreased macular pigment4, suggesting that dietary supplementation with macular pigments like lutein and zeaxanthin may be beneficial for these patients.

In summary, macular telangiectasia is a rare disorder that is often misdiagnosed. Assessment by a retina specialist with help of retinal imaging can help properly diagnose this condition, and avoid unnecessary treatments. At West Coast Retina Consultants, we are happy to have the expertise and imaging modalities to diagnose this condition.

The introduction of therapies targeting vascular endothelial growth factor (VEGF) has revolutionized the treatment of wet age-related macular degeneration (AMD). Following treatment, the majority of patients will achieve stabilization of their vision, and some may even gain visual acuity1. The two main anti-VEGF treatments are bevacizumab (Avastin) and ranibizumab (Lucentis). While there may be very subtle differences in the efficacy of these drugs, a recent randomized controlled trial has shown that they are essentially equivalent2. Although most patients do well with anti-VEGF treatment, a minority will become resistant to anti-VEGFmonotherapy3,4. These patients may require combination treatment with more than one modality. This case highlights the importance of the role of combination therapy in the treatment of wet AMD.

CASE DESCRIPTION

A 65-year old Caucasian female presented with reduced visual acuity in the right eye. Best-corrected visual acuity was 20/60 in the right eye, and 20/25 in the left eye. Intraocular pressure and slit-lamp examination were within normal limits in both eyes. Dilated fundus examination of the left eye demonstrated the presence of macular drusen. Dilated fundus examination of the right eye showed the presence of macular drusen along with a subfoveal grayish elevation (Figure 1A). Fluorescein angiography confirmed the presence of leakage at the site of elevation (Figure 1B, 1C).

Figure 1. Colour fundus photograph of the right eye showing drusen and subretinal grayish elevation (A). Early (B) and late (C) phase fluorescein angiography showing leakage from the area of elevation in the right eye.

Spectral-domain optical coherence tomography (SD-OCT) of the right macula was remarkable for the presence of subretinal fluid (Figure 2A). The patient was treated with monthly intravitreal injections of Avastin, and experienced an improvement in visual acuity to 20/40 with complete resolution of subretinal fluid (Figure 2B). However, after 6 months of monthly Avastin treatment, the subretinal fluid began to re-accumulate (Figure 2C). This fluid persisted despite repeated monthly Avastin injection, and despite a trial of monthly Lucentis. A decision was made to pursue combination therapy. She was treated with combination intravitreal Avastin and photodynamic therapy (PDT). Three months later, complete resolution of subretinal fluid was once again achieved.

Figure 2. Spectral-domain optical coherence tomography (SD-OCT) showing subretinal fluid at presentation (A). Following treatment with Avastin, the fluid completely resolved (B). However, after a few months of treatment the fluid started to re-accumulate (C). Treatment with combination therapy resulted in resolution of the fluid (D).

DISCUSSION

This case highlights several important points in the management of wet AMD and current treatment paradigms. While most patients do well with anti-VEGF monotherapy, some patients will become treatment resistant3,4. These patients can benefit from combination therapy. The high-resolution of SD-OCT allows for the early identification of these patients when they are starting to become resistant to anti-VEGF treatment, so that treatment can be altered in order to preserve visual acuity. SD-OCT using newer instruments like the Cirrus™ OCT has been shown to provide better identification of disease activity than older time-domain instruments like the Stratus™ OCT5. In fact, most retina specialists would agree that SD-OCT has surpassed older OCT technology as the benchmark diagnostic tool for the management of wet AMD. In the case of our patient, the subtle subretinal fluid that started to re-accumulate would likely not have been seen using an older time-domain OCT machine.

Various options are possible for combination therapy in wet AMD. Intravitreal steroids have a therapeutic role in wetAMD6, and the use of adjunctive intravitreal steroid would have been an option in our case. However, intravitreal steroids are associated with adverse effects including cataract and glaucoma. PDT was once the gold standard for the treatment of wet AMD. While anti-VEGF monotherapy has proven to be superior to PDT monotherapy for the treatment of wet AMD7, PDT has maintained a role in the treatment of wet AMD as an adjunct with anti-VEGF therapy8.